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The Role of Gastrokine 1 in Gastric Cancer J Gastric Cancer 2014;14(3):147-155 http://dx.doi.org/10.5230/jgc.2014.14.3.147 Review Article The Role of Gastrokine 1 in Gastric Cancer Jung Hwan Yoon, Won Suk Choi, Olga Kim, and Won Sang Park Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea Homeostatic imbalance between cell proliferation and death in gastric mucosal epithelia may lead to gastritis and gastric cancer. Despite abundant gastrokine 1 (GKN1) expression in the normal stomach, the loss of GKN1 expression is frequently detected in gastric mucosa infected with Helicobacter pylori, as well as in intestinal metaplasia and gastric cancer tissues, suggesting that GKN1 plays an impor- tant role in gastric mucosal defense, and the gene functions as a gastric tumor suppressor. In the stomach, GKN1 is involved in gastric mucosal inflammation by regulating cytokine production, the nuclear factor-κB signaling pathway, and cyclooxygenase-2 expression. GKN1 also inhibits the carcinogenic potential of H. pylori protein CagA by binding to it, and up-regulates antioxidant enzymes. In addi- tion, GKN1 reduces cell viability, proliferation, and colony formation by inhibiting cell cycle progression and epigenetic modification by down-regulating the expression levels of DNMT1 and EZH2, and DNMT1 activity, and inducing apoptosis through the death receptor- dependent pathway. Furthermore, GKN1 also inhibits gastric cancer cell invasion and metastasis via coordinated regulation of epithelial mesenchymal transition-related protein expression, reactive oxygen species production, and PI3K/Akt signaling pathway activation. Although the modes of action of GKN1 have not been clearly described, recent limited evidence suggests that GKN1 acts as a gastric- specific tumor suppressor. This review aims to discuss, comment, and summarize the recent progress in the understanding of the role of GKN1 in gastric cancer development and progression. Key Words: GKN1 protein; Homeostasis; Gastritis; Stomach neoplasms; Tumor suppressor gene Introduction ingested noxious agents, and acidic pH, may lead to diseases such as gastritis and gastric cancer. Therefore, protective and reparative Generally, the gastrointestinal epithelium is characterized by mechanisms are essential to rapidly restore gastric mucosal integrity a very high cellular turnover rate, which leads to renewal of the by stimulating migration of epithelial cells over denuded areas (res- epithelium every 3 to 5 days.1 Continuous processes of cell prolif- titution), increasing mucus production, and reestablishing epithelial eration, differentiation, and self-renewal are counterbalanced by proliferation and differentiation programs.2 Although endogenous senescence and/or apoptosis in normal gastric mucosa. To maintain molecules, such as members of the trefoil factor 1 protein family, homeostasis, a critical balance between cell proliferation and death protect the gastric mucosa from noxious environments,3 many of is required, and complex signaling pathways and transcriptional their underlying molecular mechanisms have not been clearly elu- regulators control it. Otherwise, homeostatic imbalance, caused cidated. by several factors, including infection with Helicobacter pylori, Gastrokine 1 (GKN1), also called antral mucosal protein (AMP)-18, is a protein synthesized by the cells of the antral gastric Correspondence to: Won Sang Park mucosa and shows growth factor or ‘cytokine-like’ activity toward Department of Pathology, College of Medicine, The Catholic University 4 of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea gastric epithelial cells. Immunoelectron microscopy indicated that Tel: +82-2-590-1192, Fax: +82-2-537-6586 the GKN1 protein is localized within the granules just under the E-mail: [email protected] apical plasma membrane, suggesting that it is a secreted rather Received August 12, 2014 4 Revised September 12, 2014 than an integral membrane protein. Early work reported that Accepted September 13, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyrights © 2014 by The Korean Gastric Cancer Association www.jgc-online.org 148 Yoon JH, et al. GKN1 protects the antral gastric mucosa and promotes healing by hydrophobic region and BRICHOS domain of GKN1, but not the facilitating restitution and proliferation following injury.4 Interest- COOH-terminal region, significantly reduce cell viability, prolif- ingly, this protein is abundantly expressed in the gastric mucosa of eration, and colony formation of AGS gastric cancer cells by regu- healthy individuals, but is down-regulated or absent in gastric can- lating cell cycle progression, and minimize epigenetic modification cer tissues.4 Because a disruption in gastric homeostasis may result by inhibiting the expression of DNMT1 and EZH2, and DNMT1 in the transformation of normal epithelial cells into cancer cells and activity. Therefore, these findings indicate that the NH2-terminal permit cancer cells to proliferate and invade, there is no doubt that hydrophobic region and BRICHOS domain of GKN1 might be the inactivation of GKN1 may render the gastric mucosa vulnerable to main functional domain for tumor suppressor activity.12 carcinogens or gastric injury, and eventually trigger genetic altera- Two isoforms of the GKN1 protein with different NH2- tions in cancer-related genes, including oncogenes and tumor sup- terminal residues, aspartic acid (D) and asparagine (N), were found pressor genes. in gastric endoscopy biopsy samples, and the isoform containing Although limited published evidence suggests that GKN1 may asparagine was decreased or absent in some H. pylori-positive play an important role in gastric epithelial homeostasis and gastric patients.13 Therefore, these two isoforms might play different roles carcinogenesis, its definitive biological functions remain unclear. In in H. pylori-infected gastric mucosa. Previously, we reported that this review, we discuss the current understanding of the biological an aspartic acid or asparagine variant at codon 13 in the NH2- roles of the GKN1 tumor suppressor in the development and pro- terminal region, but not alanine variant of the pGKN1D13A mutant, gression of gastric cancer. was found to be important in the anti-growth function of GKN1.12 Therefore, it seems that genetic alterations or loss of expression Characteristics of Gastrokine 1 of the NH2-terminal hydrophobic region and BRICHOS domain of GKN1 might lead to the functional inactivation of the GKN1 The protein, previously known as AMP-18, CA11, FOVEO- protein. However, to explain how GKN1 expression is controlled LIN, and TFIZ,5-8 was formally named ‘GKN1’ by the HUGO in normal gastric mucosa, further studies are important to delineate Gene Nomenclature Committee (HGNC no. 23217) for its gastric- the molecular mechanisms regulating transcription and biological specific expression and its highly conserved presence in the gastric roles of GKN1 in gastric mucosal epithelia. mucosa of many mammalian species.5,6 Three members of the GKN family, GKN1, GKN2, and GKN3, are located on chro- Gastrokine 1 in Non-Neoplastic mosome 2p13.3 and arranged within a 60-kb genomic interval.9 Gastric Mucosa The structures of the GKN genes exhibit nearly identical genomic architecture, with each containing six exons separated by relatively GKN1 is a unique gastric-specific protein, whose expres- short introns.9 GKN genes encode small (from 181- to 184-amino sion is confined to the gastric epithelium, except for trace levels acid) proteins; and contain the enigmatic BRICHOS domain and in the uterus and placenta.5 GKN1 protein and mRNA are local- a COOH-terminal segment showing considerable divergence be- ized in surface mucous cells of the gastric antrum and fundus in 6,13-16 tween the GKN paralogs and the hydrophobic NH2-terminal sig- humans. GKN1 is involved in filling the lumen of the surface nal peptide, the processing of which is predicted to generate about layer of epithelial cells to maintain mucosal integrity and regulate 160 mature amino acid proteins with a molecular mass of approxi- cell proliferation and differentiation.5,6 In addition, GKN1 is present 9,10 mately 18 kDa. Of these, the NH2-terminal hydrophobic region in the secretion granules of gastric mucosal epithelial cells during acts as a transmembrane anchor and/or signal peptide.10 Clinically, immunogold-labeling experiments4 and, therefore, is predicted to the proteins in the BRICHOS superfamily are associated with de- function as a secreted protein acting primarily in the extracellular mentia, respiratory distress syndrome, and cancer.10,11 Molecular and luminal environment.9 As mentioned earlier, the gastrointes- studies on the BRICHOS domain function have suggested that it tinal epithelium is characterized by a very high cellular turnover has a range of possible roles, including intracellular trafficking, pro- rate, which leads to renewal of the epithelium every 3 to 5 days.1 peptide processing, chaperone function, and secretion.11 However, GKN1 also facilitates regeneration of the injured colonic epithelium the biological activities of the BRICHOS domain in GKN1 have by accelerating migration of surviving cells at the edges of wounds, not been elucidated. We previously reported that the NH2-terminal and also
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